Bryant Camron D, Eitan Shoshana, Sinchak Kevin, Fanselow Michael S, Evans Christopher J
Interdepartmental Program in Neuroscience, Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, CA 90024, USA
Am J Physiol Regul Integr Comp Physiol. 2006 Aug;291(2):R315-26. doi: 10.1152/ajpregu.00831.2005. Epub 2006 Apr 6.
Multiple studies demonstrate that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with the opioid agonist morphine attenuates the development of analgesic tolerance. Sex differences in the effects of noncompetitive, but not competitive NMDA receptor antagonists on acute morphine analgesia, have been reported in mice, yet the role of sex in modulation of morphine tolerance by NMDA receptor antagonists has yet to be addressed. Therefore, we tested whether there is a sex difference in the effect of NMDA receptor antagonists on the development of morphine analgesic tolerance in C57BL/6J mice. Acutely, at a dose required to affect morphine tolerance in male mice, the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) prolonged morphine analgesia similarly in both sexes in the hot plate and tail withdrawal assays. In the hot plate assay, coadministration of MK-801 or the competitive antagonist 3-(2-carboxpiperazin-4-yl)propyl-1-phosphanoic acid (CPP) with morphine attenuated the development of tolerance in male mice, while having no effect in females. Like normal and sham females, ovariectomized mice were similarly insensitive to the attenuation of morphine tolerance by MK-801 in the hot plate assay. Surprisingly, in the tail withdrawal assay, MK-801 facilitated the development of morphine-induced hyperalgesia and tolerance in males but not females. The results demonstrate that male mice are more sensitive to modulation of nociception and morphine analgesia after repeated coadministration of NMDA receptor antagonists. Furthermore, the underlying mechanisms are likely to be different from those mediating the sex difference in the modulation of acute morphine analgesia that has previously been reported.
多项研究表明，将N-甲基-D-天冬氨酸（NMDA）受体拮抗剂与阿片类激动剂吗啡联合使用可减弱镇痛耐受性的发展。在小鼠中，已报道非竞争性而非竞争性NMDA受体拮抗剂对急性吗啡镇痛作用存在性别差异，但NMDA受体拮抗剂在调节吗啡耐受性方面的性别作用尚未得到研究。因此，我们测试了NMDA受体拮抗剂对C57BL/6J小鼠吗啡镇痛耐受性发展的影响是否存在性别差异。急性给药时，在影响雄性小鼠吗啡耐受性所需的剂量下，非竞争性NMDA受体拮抗剂地佐环平（MK-801）在热板和甩尾试验中对两性的吗啡镇痛作用延长相似。在热板试验中，MK-801或竞争性拮抗剂3-(2-羧基哌嗪-4-基)丙基-1-膦酸（CPP）与吗啡联合给药可减弱雄性小鼠耐受性的发展，而对雌性小鼠无影响。与正常和假手术雌性小鼠一样，去卵巢小鼠在热板试验中对MK-801减弱吗啡耐受性同样不敏感。令人惊讶的是，在甩尾试验中，MK-801促进了雄性而非雌性小鼠吗啡诱导的痛觉过敏和耐受性的发展。结果表明，重复联合使用NMDA受体拮抗剂后，雄性小鼠对伤害性感受和吗啡镇痛的调节更敏感。此外，其潜在机制可能与先前报道的调节急性吗啡镇痛的性别差异机制不同。
